Cross-relaxation imaging (CRI) is a new quantitative method of magnetic resonance imaging (MRI), which allows the measurement and in vivo mapping of two key parameters determining nuclear magnetic interactions between water and macromolecules in tissues - the macromolecular proton fraction and cross-relaxation rate constant. The general objectives of this project are to tailor the CRI technology to serial clinical usage based on a 3T imaging platform and to demonstrate the feasibility of serial clinical applications with a particular focus on multiple sclerosis (MS). The project contains three specific aims. In the first aim, a fast, accurate, and reliable whole-brain CRI data acquisition technology will be developed for serial clinical applications. The research design will include a combined application of CRI with fast methods for magnetic and radiofrequency field correction, development of the sequence with improved time efficiency by using parallel acquisition and segmented echo-planar signal readout, and optimization of a sampling scheme for the best measurement accuracy. In the second aim, a comprehensive methodology of cross-relaxation image processing and analysis will be developed. This methodology will produce a series of potential biomarkers for the characterization of pathological changes in brain tissues on both global and regional levels. The research design will include the development of the image processing algorithm, which will combine the reconstruction of parametric maps and tissue segmentation followed by histogram analysis. This will result in a series of quantitative metrics, characterizing distributions of cross-relaxation parameters in the entire brain, white matter, gray matter, lesions, and clinically relevant white matter fiber tracts. In the third aim, a clinical study will be conducted to test the general hypothesis that quantitative imaging biomarkers derived from CRI are sensitive to pathological changes in brain tissues caused by MS and are associated with the patients'clinical status and the course of the disease. CRI will be performed on groups containing 50 MS patients (25 with relapsing-remitting and 25 with secondary progressive disease course) and 25 healthy controls. Statistical analysis will be conducted to compare prospective imaging biomarkers between groups and to test associations between imaging biomarkers and commonly accepted MS clinical status scales. A probable outcome of this project is that CRI will provide new biomarkers with high sensitivity and specificity to pathological brain tissue changes in MS. Such biomarkers are of high interest as surrogate endpoints in therapeutic clinical trials. The technical solutions and basic knowledge gained in this project will be useful for other potential areas of CRI application, such as neurodegenerative, vascular, and neoplastic CNS disorders. PUBLIC HEALTH RELEVANCE: This project aims to develop a new quantitative method of magnetic resonance imaging for measurements of key parameters determining magnetic interactions between water and macromolecules in tissues. This method is expected to be highly beneficial for monitoring of disease progression and treatment effects in multiple sclerosis and other neurological disorders. This study also will lead to improved understanding of a relationship between disability progression and neural tissue damage in multiple sclerosis.